1. Field of the Invention
The present invention relates to an adeno-associated virus vector expressing Aβ peptide, which can be used for the treatment of Alzheimer's disease, and its use as a pharmaceutical agent.
2. Background Art
Alzheimer's disease is characterized by senile (neuritic) plaques, neurofibrillary tangles, and the alteration and depletion of neural cells in the brain. In particular, β-amyloid deposited in senile plaques is considered to play a central role in pathological development of Alzheimer's disease. β-Amyloid peptide (Aβ), the major component of this β-amyloid deposit, is produced by partial decomposition of β-amyloid precursor protein (βAPP) by β- and γ-secretases in neural cells.
Recently, it is disclosed that the formation of senile plaques was suppressed and the number of existing senile plaques was reduced by administering Aβ peptide along with an adjuvant for immunization to transgenic mice which have familial forms of Alzheimer pathology and overexpress a human amyloid precursor protein (Schenk D., Barbour R., Dunn W. et al.: Nature 400:173-177, 1999).
As putative mechanisms for the abovementioned reactions, three theories are now proposed. According to the first theory, the antibody against Aβ produced in the body by Aβ peptide administration binds the aggregated Aβ in senile plaques and microglial phagocytosis of the resulting product elicits the clearance of the senile plaques. The antibody also binds secreted Aβ and microglial phagocytosis of the resulting product elicits the suppression of cytotoxicity of Aβ to neural cells. These lead to the treatment of dementia and the like. According to the second theory, the antibody against AD produced by Aβ peptide administration binds Aβ by recognizing its N terminus amino acid to solubilize aggregated or insolubilized Aβ and further to suppress aggregation and deposition of secreted Aβ, which results in the reduction in amyloid deposition. According to the third theory, so-called “sink” theory, the antibody against Aβ does not pass through the blood-brain barrier but it diffuses Aβ from the central nerve system to the peripheral system by reducing Aβ in the peripheral blood and peripheral tissue.
Based on the abovementioned theories, development of preventive and therapeutic methods for Alzheimer's disease has also been attempted with virus vectors. For example, it is described that oral administration of an adenovirus vector, in which Aβ cDNA is incorporated, to C57BL/6 mice enabled Aβ to be expressed in the tissues of the upper gastrointestinal tract in the mice and that the anti-Aβ antibody in the mouse serum inhibited the aggregation of Aβ peptide in vitro (Takeshi Tabira and Hideo Hara, Fiscal 2002 Welfare Science Research, “21 Century-Type Medical Pioneering/Promoting Research (Field of Dementia), Publication Report on Research Results” published by Incorporated Foundation, Japan Foundation for Longevity Science (Choju Kagaku Shinko Zaidan), March 2002, pp. 49-54). In this report, however, no in vivo experiment has been reported and therapeutic effect in animals has not been confirmed.
Furthermore, it is known that the cytokine TGF-β1 (transforming growth factor β1) promotes the production of inflammatory cytokines (IL-1β (interleukin-1β), TNF-α (tumor necrosis factor-α and the like) in vascular endothelial cells. Further, recently, it was reported that TGF-β1 promoted Alzheimer's disease-related pathological changes such as cerebrovascular amyloid deposition and microvascular degeneration (Wyss-Coray, T. et al.: Amyloidogenic role of cytokine TGF-β1 in transgenic mice and Alzheimer's disease: Nature 389: 603-606, 1997 and Wyss-Coray, T. et al.: Chronic overproduction of transforming growth factor-β1 by astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice: Am. J. Pathol. 156: 139-150, 2000).
Therapeutic agents for Alzheimer's disease have to suppress senile plaque formation and amyloid deposition in the central nervous system and at the same time should not diffuse into other organs or cause side effects such as encephalitis for safety. However, no therapeutic agent to meet these requirements utilizing the Aβ antigen has so far been reported.